Transient ischemic attacks (TIAs) are common, affecting over 300,000 persons per year in the United States alone. Though TIA symptoms resolve by definition, TIAs are far from benign. As many as 25% of TIA patients have recurrent ischemic vascular events that occur within days to weeks following a TIA (1-3). Despite the high incidence and clinical importance, the development of therapies specifically targeted toward TIA has been limited by the paucity of knowledge regarding the underlying biology. Furthermore, the clinical diagnosis of TIA is imperfect and extensive evaluation in those incorrectly diagnosed with TIA is costly (4).
We have previously demonstrated that blood gene expression profiles in rats change following experimental ischemic strokes and TIAs (5). Very brief focal ischemia in rats, simulating human TIA, elicits a dramatic change in brain tissue characterized by increased Heat Shock Protein (HSP70) expression, microglial activation and macrophage infiltration (6). This change in brain cellular function and inflammation alters blood immune cells, a process that can be detected using whole genome expression analysis (5). Furthermore, the genes and associated functional pathways differ markedly between very brief focal ischemia and ischemic stroke (5).
Human TIAs have also been associated with alterations in systemic inflammation. TIA patients tend to have elevated C-reactive protein (CRP) (7), IL-6, VCAM-1 and cytokine levels, as well as elevated leukocyte counts (8-10). Lp-PLA2, a marker of unstable atherosclerotic plaque, is also associated with TIA (11-12) as are fibrinogen (13-14) and D-Dimer (15). Whether such biological differences represent a cause or consequence of TIA remains unclear. However, better understanding of the pathophysiology represented by such differences will facilitate development of treatments targeted to TIA.
Gene expression has been useful for identifying differences between patients with ischemic stroke and controls (16-18), but such studies have not been applied to TIA. The present invention is based, in part, on gene expression profiles that provide insight into the immunological differences that exist in patients with TIAs.